The present invention discloses 4-oxo-4,7-dihydrothieno[2,3-b)pyridine-5-carboxamides derivatives, and more specifically, provides compounds of formula (I) described herein below. These compounds are useful as antiviral agents, in particular, as age nts against viruses of the herpes family.
The herpes viruses comprise a large family of double stranded DNA vies. They are also a source of the most common viral illnesses in man. Eight of the herpes viruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8), have been shown to infect humans.
HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals, respectively. They also occasionally cause infections of the eye and encephalitis. HCMV causes birth defects in infants and a variety of diseases in immunocompromised patients such as retinitis, pneumonia, and gastrointestinal disease. HCMV infection is also associated with cardiovascular disease and conditions including restenosis and atherosclerosis. VZV is the causative agent of chicken pox and shingles. EBV causes infectious mononucleosis. It can also cause lymphomas in immunocompromised patients and has been associated with Burkitt""s lymphoma, nasopharyngeal carcinoma, and Hodgkins disease. HHV-6 is the causative agent of roseola and may be associate with multiple sclerosis and chronic fatigue syndrome. HHV-7 disease association is unclear, but it may be involved in some cases of roseola. HHV-8 has been associated with Karposi""s sarcoma, body cavity based lymphomas, and multiple myeloma.
Infection by or reactivation of herpesviruses is associated with several cardiovascular diseases or conditions in the host such as atherosclerosis and restenosis resulting in inflation of coronary vessel walls. It is thought that in many patients suffering from restenosis following coronary atherectomy viral infection particularly by CMV plays an important role in the proliferation of the disease. Atherosclerosis is believed to be associated with the overall infectious disease burden in the host and particularly by the herpesviruses such as HSV, CMV, and EBV.
Infection in the animal population (livestock and companion) by strains of herpesviruses is endemic including cattle (Bovine herpesvirus 1-5, BHV), sheep (Ovine herpesvirus 1 and 2), dog (Canine herpesvirus 1), horse (Equine herpesvirus 1-8, EHV), cat (Feline herpesvirus 1, FHV), swine (pseudorabies virus, PRV), and many species of fowl. In the case of bovine herpesvirus infection, animals may suffer from ocular, respiratory, or digestive disorders. Pseudorabies is an extremely contagious viral pathogen infecting several species such as cattle, horses, dogs, cats, sheep, and goats leading to rapid death. The virus is benign in adult swine, however, it remains contagious and leads to high mortality in pigs under three weeks. Infection of horses by equine herpesvirus may lead to neurological syndromes, respiratory disease, and neonatal disease. Herpesvirus infection in cats leads to the disease known as feline viral rhinotracheitis (FVR) which is characterized by rhinitis, tracheitis, laryngitis, and conjunctivitis.
Compounds of the present invention demonstrate unexpected activity against the above reference herpesviral infections, particularly, human cytomegaloviral infection.
U.S. Pat. No. 6,239,142 discloses compounds and their use to treat herpesvirus infections.
EP 443568 discloses compounds having angiotensin II antagonist activity and antihypertensive activity. WO95/28405 discloses compounds potentially useful for the treatment of sex-hormone dependent cancers and as contraceptives.
JP 08301849 discloses compounds useful as tachykinin receptor antagonists.
The present invention provides a compound of formula I: 
its enantiomeric, diastereomeric, or tautomeric isomer thereof, or a pharmaceutically acceptable salt thereof wherein,
G is phenyl substituted with from one (1) to five (5) R1 substituents;
each R1 is independently
(a) Cl,
(b) Br,
(c) F,
(d) CN,
(e) C1-7alkyl, or
(f) NO2;
R1 is
(a) H,
(b) R5,
(c) NR7R8,
(d) SO2R10, or
(e) OR9;
A is C1-7alkyl;
W is a five- (5) or six- (6) membered heterocyclic ring having one (1), two (2) or three (3) heteroatoms selected from the group consisting of O, S(O), and N wherein W is optionally substituted with one or more OH, oxo (xe2x95x90O), or C1-7 alkyl;
B is
(a) C1-7alkyl optionally substituted by OH or NR7R8,
(b) O, or
(c) NR11;
R3 is
(a) phenyl, optionally fused to a benzene or pyridine ring, and optionally substituted by R12, wherein optionally any two adjacent R12 substituents taken together constitute a group of the formula xe2x80x94O(CH2)Oxe2x80x94, xe2x80x94(WC(xe2x95x90O)(CH2)jOxe2x80x94, or CH2)ixe2x80x94, or
(b) a five- (5) or six- (6) membered heteroaryl bonded via a carbon atom having one (1), two (2), or three (3) heteroatoms selected from the group consisting of O, S, and Nxe2x80x94Z, wherein R3 is optionally fused to a benzene or pyridine ring, and optionally substituted with one or more R12, wherein Z is absence, H, or C1-4alkyl;
R4 is
(a) H,
(b) halo, or
(c) C1-4alkyl optionally substituted by halo;
R5 is
(a) (CH2)mOCH2CH2OR11,
(b) het, wherein said het is bound via a carbon atom,
(c) aryl,
(d) C1-7alkyl which may be partially unsaturated and is optionally substituted by one or more R6 substituents, or
(e) C3-8 cycloalkyl which may be partially unsaturated and optionally substituted by one or more R6 or C1-7alkyl optionally substituted by R6;
R6 is
(a) OR9,
(b) SR9,
(c) NR7R8,
(d) halo,
(e) CONR7R8,
(f) CO2R9,
(g) het,
(h) phenyl, optionally substituted by R12,
(i) CN,
(j) oxo,
(k) SO2NR9R11,
(l) SOm R10, or
(m) P(xe2x95x90O)(OR11)(R11;
R7 and R8 are independently
(a) H,
(b) aryl
(c) C1-7 alkyl which may be partially unsaturated and is optionally substituted by one or more NR11R11, OR11, SR11, SOmR10, CONR11Rll, CO2R11, het, aryl, cyano, or halo,
(d) C3-8cycloalkyl,
(e) (Cxe2x95x90O)R10, or
(f) R7 and R8 together with the nitrogen to which they are attached form a het;
R9 is
(a) H,
(b) aryl,
(c) het, wherein the het is bound through a carbon atom,
(d) C1-7alkyl which is optionally partially unsaturated and is optionally substituted by one or more aryl het, OR11, SR11NR11R11, halo, or C3-8cycloalkyl substituents and which C3-8cycloalkyl is optionally substituted by OR11, or
(e) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more halo, OR11, SR11, or NR11R11substituents;
R10 is
(a) aryl,
(b) bet,
(c) C1-7alkyl which is optionally partially unsaturated and is optional substituted by one or more aryl, bet, OR11, SR11, NR11R11, halo, or C3-8cycloalkyl substituents and which C3-8 cycloalkyl is optionally substituted by OR11, or
(d) C3-8 cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more halo, OR11, SR11, or NR11R11 substituents;
R11 is
(a) H, or
(b) C1-7alkyl;
R12 is
(a) halo,
(b) OR14,
(c) SR11,
(d) NR7R8,
(e) phenyl, optionally substituted by halo, C1-7alkyl, or C1-7alkoxy,
(f) C1-7alkyl which is optionally partially unsaturated and optionally substituted by R13,
(g) cyano,
(h) nitro,
(i) CONR7R8,
(j) SO2NR7R8,
(k) CO2R11, or
(l) NHC(xe2x95x90O)R11;
R13 is
(a) phenyl, optionally substituted by halo, C1-7alkyl, or C1-7alkoxy,
(b) OR11,
(c) O(CH2CH2O)nR11,
(d) NR7R8, or
(e) halo;
R14 is
(a) H
(b) alkyl, optionally substituted by halo,
(c) phenyl, optionally substituted by halo, C1-7alkyl, or C1-7alkoxy, or
(d) xe2x80x94(CH2CH2O)nOR11;
i is 3 or 4;
j is 0 or 1;
k is 0, 1, or 2;
each n is independently 1, 2, 3, 4 or 5;
each m is independently 1 or 2;
wherein any aryl is optionally substituted with one or more substituents selected from the group consisting of halo, OR11, NR11R11, cyano, CO2R11, or C1-7alkyl in which said C1-7allyl is optionally substituted by one to three halo, OR11, or NR11R11; and
wherein any het is optionally substituted with one or more substituents selected from the group consisting of halo, OR11, NR11R11, cyano, CO2R11, oxo (xe2x95x90O), or C1-7alkyl in which said C1-7alkyl is optionally substituted by one to three halo, OR11, or NR11R11.
In another aspect, the present invention also provides:
A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I,
a method of treating and preventing herpesviral infections in a mammal comprising administering to a mammal in need thereof a compound of formula I, or a pharmaceutically acceptable salt thereof,
a method for inhibiting a viral DNA polymerase comprising contacting, in vivo or in vitro, the polymerase with an effective inhibitory amount of a compound of formula I, or a pharmaceutically acceptable salt thereof,
a compound of formula I or a pharmaceutically acceptable salt thereof for use in medical treatment or prevention of a herpesviral infection in a mammal.
The invention also provides novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I.